DESCRIPTION: (Applicant's Abstract) The neuronal mechanisms underlying the development of opioid tolerance and dependence have eluded researchers for decades. Recent investigations of a novel pharmacological class of compounds, called neutral antagonists, indicate that these compounds may attenuate effects produced by agonists but fail to produce effects of their own. In addition, neutral antagonists appear to reverse the effects produced by traditional antagonists in vivo and in vitro. A class of somatostatin analogues has been synthesized that includes selective high-affinity opioid ligands that may be candidates as neutral antagonists for the mu-opioid receptor. A few current reports have indicated that these purported neutral antagonists reverse opiate withdrawal produced by traditional mu-opiate receptor antagonists. The goal of the proposed experiments is to evaluate the behavioral and pharmacological properties of the putative neutral antagonists in nondependent and morphine-dependent rats using a variety of analgesia and drug discrimination procedures. By providing the first systematic evaluation of the behavioral effects of neutral antagonists, these studies could radically alter the manner in which we think about opioid receptor pharmacology. Furthermore, because these drugs block the effects of mu opioids, but do not precipitate withdrawal, the findings of these experiments will be highly relevant to the treatment of opioid dependence.